1. Field of the Invention
The present invention is directed to a process for making 2,5-substituted pyridine compounds. In particular, this invention is directed to a process for making 2,5-substituted pyridine compounds utilizing butyllithium in order to produce a 2-electrophile 5-halo substituted pyridine.
2. Related Background
Hormones are compounds that variously affect cellular activity. In many respects, hormones act as messengers to trigger specific cellular responses and activities. Many effects produced by hormones, however, are not caused by the singular effect of just the hormone. Instead, the hormone first binds to a receptor, thereby triggering the release of a second compound that goes on to affect the cellular activity. In this scenario, the hormone is known as the first messenger while the second compound is called the second messenger. Cyclic adenosine monophosphate (adenosine 3xe2x80x2,5xe2x80x2-cyclic monophosphate, xe2x80x9ccAMPxe2x80x9d or xe2x80x9ccyclic AMPxe2x80x9d) is known as a second messenger for hormones including epinephrine, glucagon, calcitonin, corticotrophin, lipotropin, luteinizing hormone, norepinephrine, parathyroid hormone, thyroid-stimulating hormone, and vasopressin. Thus, cAMP mediates cellular responses to hormones. Cyclic AMP also mediates cellular responses to various neurotransmitters.
Phosphodiesterases (xe2x80x9cPDExe2x80x9d) are a family of enzymes that metabolize 3xe2x80x2,5xe2x80x2 cyclic nucleotides to 5xe2x80x2 nucleoside monophosphates, thereby terminating cAMP second messenger activity. A particular phosphodiesterase, phosphodiesterase-4 (xe2x80x9cPDE4xe2x80x9d, also known as xe2x80x9cPDE-IVxe2x80x9d), which is a high affinity, cAMP specific, type IV PDE, has generated interest as potential targets for the development of novel anti-asthmatic and anti-inflammatory compounds. PDE4 is known to exist as at lease four isoenzymes, each of which is encoded by a distinct gene. Each of the four known PDE4 gene products is believed to play varying roles in allergic and/or inflammatory responses. Thus, it is believed that inhibition of PDE4, particularly the specific PDE4 isoforms that produce detrimental responses, can beneficially affect allergy and inflammation symptoms.
Inhibition of PDE4 activity is believed effective for the treatment of osteoporosis by reducing bone loss. For example, Ken-ici Miyamoto et al., Biochem. Pharmacology, 54:613-617(1997) describes the effect of a PDE4 on bone loss. Therefore, it would be desirable to provide novel compounds and compositions that inhibit PDE4 activity.
Novel compounds and compositions that inhibit PDE4 activity remain desirable. Further, more efficient methods to produce known PDE4 inhibiting compounds are a continuing need.
U.S. Pat. Nos. 5,491,147, 5,608,070, 5,622,977, 5,739,144, 5,776,958, 5,780,477, 5,786,354, 5,798,373, 5,849,770, 5,859,034, 5,866,593, 5,891,896, and International Patent Publication WO 95/35283 describe PDE4 inhibitors that are tri-substituted aryl or heteroaryl phenyl derivatives. U.S. Pat. No. 5,580,888 describes PDE4 inhibitors that are styryl derivatives. U.S. Pat. No. 5,550,137 describes PDE4 inhibitors that are phenylaminocarbonyl derivatives. U.S. Pat. No. 5,340,827 describes PDE4 inhibitors that are phenylcarboxamide compounds. U.S. Pat. No. 5,780,478 describes PDE4 inhibitors that are tetra-substituted phenyl derivatives. International Patent Publication WO 96/00215 describes substituted oxime derivatives useful as PDE4 inhibitors. U.S. Pat. No. 5,633,257 describes PDE4 inhibitors that are cyclo(alkyl and alkenyl)phenyl-alkenyl (aryl and heteroaryl) compounds.
In many of the processes to produce the compounds described in the above patents and publications, various intermediate compounds are utilized. In particular, 2-electrophile-5-halopyridine intermediate compounds derived from a 2-lithio-5-halopyridine have utility and novel processes to produce such intermediate compounds are desirable.
C. Bolm, et al., Chem. Ber. 125:1169(1992); F. C. Alderweireldt, et al., Nucleosides Nucleotides, 8:891(1989); J. Wicha and M. Masnyl, Heterocycles, 16:521(1981); and F. J. Romero-Salguero and J. M. Lehn, Tetrahedron Lett., 37:2357(1996), describe reactions utilizing coordinating solvents such as ether, MTBE, and THF to cause lithiation at the 5-position, or mixed monolithiation at the 5- and 2-positions, with predominantly lithiation at the 5-lithiated position. M. A. Peterson and J. Mitchell, J.Org.Chem.,62:8237(1997) describes how solvents can influence the formation, structure, and properties of organolithiums. Nevertheless, 2-electrophile-5-halopyridine intermediate compounds derived from a 2-lithio-5-halopyridine are particularly desirable and novel processes to produce such intermediate compounds efficiently are desirable.
The present invention is directed to a novel method to produce a 2-electrophile-5-halopyridine compound which includes the steps of i) selective monolithiation at the 2 position of 2,5-dihalopyridine with butyllithium to form a 2-lithio-5-halopyridine and ii) replacing the lithio group with an electrophilic group to form the 2-electrophile-5-halopyridine compound.
A method of this invention comprises the steps of
A) reacting a compound represented by (I) 
wherein X is independently bromine or iodine, with an effective amount of BuLi in an effective amount of a non-coordinating solvent at a temperature from about xe2x88x9250xc2x0 C. to about xe2x88x9278xc2x0 C. to form a compound represented by (II) 
and
B) reacting (II) with an effective amount of an electrophilic reactant represented by E+ effective to replace the Li with an electrophile represented by E effective to form a compound represented by (III) 
The halogen, X, is independently iodine or bromine. It is preferred that the halogen is bromine. It is preferred that the compound (I) is 2,5-dibromopyridine.
As used herein, xe2x80x9ccoordinating solventsxe2x80x9d are solvents with oxygen or nitrogen atoms in the solvent molecule. Such solvents are available for coordinating with BuLi or pyridinyl lithium. As used herein, xe2x80x9cnon-coordinating solventsxe2x80x9d are solvents that do not have oxygen or nitrogen atoms for coordination with BuLi or pyridinyl lithium.
As reported in C. Bolm, et al., Chem. Ber. 125:1169(1992); F. C. Alderweireldt, et al., Nucleosides Nucleotides, 8:891(1989); J. Wicha and M. Masnyl, Heterocycles, 16:521(1981); and F. J. Romero-Salguero and J. M. Lehn, Tetrahedron Lett., 37:2357(1996), coordinating solvents such as, for example, ether, MTBE, and THF caused lithiation at the 5-position or a mixture of monolithiation at the 5- and 2-positions with predominantly lithiation at the 5-lithiated position.
However, the method of this invention surprisingly found that the use of noncoordinating solvents such as, for example, toluene or methylene chloride produced monolithiation predominantly at the 2-position. Accordingly, this invention forms a reaction product mixture that contains predominantly 2-lithio-5-halopyridine. By predominantly, it is meant that the 2-lithio-5-halopyridine is the largest percent component by weight. Unless specifically stated otherwise, the percentages stated herein are by weight.